We propose a five-year study to examine the familial transmission of substance abuse using the techniques of genetics, epidemiology, and clinical psychiatry. The basic design of the study involves a combination of the family study and longitudinal high risk paradigms. By investigating the patterns of familial transmission of substance abuse, we will study the association of psychiatric disorders with sedative, hypnotic, or anxiolytic abuse. Transmission and non-transmissible risk factors will also be identified to examine the mechanisms of the links between abuse of these substances and psychopathology. A cohort of offspring of these proband groups who are presumed to be at increased risk for developing substance abuse will be studied prospectively to examine the longitudinal course of the development of substance abuse in relation to pre-existing psychopathology. The prospective design will also enable us to discriminate antecedent risk factors from consequences of drug abuse. Possible mechanisms for the associations between psychiatric disorders and substance abuse can then be identified without being confounded by retrospective recall bias. Specifically, in the proposed study we will: 1) obtain samples of probands with a history of sedative, hypnotic, or anxiolytic abuse or dependence, probands with anxiety disorders, and normal controls; 2) collect detailed information on the probands, spouses, and first-degree relatives; and 3) study a sample of their offspring longitudinally with comprehensive assessment of social and demographic factors, psychopathology, and psychological and neurophysiological functioning during the five-year period. The findings derived from the proposed study will have important implications in the following areas: identification of patterns of familial aggregation of substance abuse specification of the associations and possible mechanisms for the co-occurrence of substance abuse and other psychiatric disorders; identification of pre-clinical signs and risk factors for substance abuse; investigation of whether the neurophysiological markers in subjects at high risk for alcoholism generalize to abuse of other substances; and identification of susceptible persons and possible areas of intervention, with the ultimate goal being primary prevention of substance abuse.